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Results for “Cell Self Renewal”

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At least 19 recordsLinked to original sources
PubMed1986

Does stem cell self renewal and progenitor cell commitment operate through an effector-memory cell mechanism?

We propose a model for stem cell self renewal and transition into commitment towards a variety of cell lineages. In this model the production of both "effector cells" (as represented by the mature cells in the different cell lineages) and of progenitor "memory" lymphocytes, takes place concomitantly. The experimental evidence supporting this model is as follows: Pure lymphocytic suspensions (PLS) are established and persist in culture when nude mouse-spleen and lymph-node cells are maintained on X-irradiated fibroblast monolayers in the presence of the S-phase cytotoxic agent cytosine arabinoside (Ara-C). From these PLS the following colony types can be initiated by the corresponding inducing (stimulating) factors (CSF): histiocytes (tissue macrophages) - CSF-1; granulocytes-macrophages (GM) - CSF-GM; mast cells - MMSF; granular-NK mucus secreting cells - IL-2; and multilineage colonies - IL-3. Mitotically active blast cells (formed by transformation of lymphocytes), condense into motile small cells when the stimulatory factor is removed. These "memory" lymphocytes are committed as they carry the receptors for the specific CSF; they respond by retransformation into blast cells. A dramatic increase in mast-cell colony forming cells is found in bone marrow, spleen and lymph-nodes of mice infected with Schistosoma mansoni. By maintaining PLS with both Ara-C and each of the CSFs and then titrating the incidence of CFC in the residual PLS, we find that each one of the CSFs acts on an independent set of cells in the PLS to produce the corresponding colony type. Finally, the concept suggests that the various blast cells carrying the receptors, undergo condensation into memory lymphocytes when dissociated from the environment prevailed by the corresponding CSF. In this way pluripotential blast-cells condense into motile lymphocytes which are committed to pluripotentiality.

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PubMed1988

Permanent loss in stem cell self renewal capacity following stress to the marrow.

A technique of irradiating the entire mouse except for one hind limb was developed to provide repeated proliferative demand on the stem cell pool. Animals received 200 cGY weekly for a total dose of 3,400 to 4,000 cGy. During irradiation, shielded bone marrow cellularity was similar to that of unirradiated controls. Shielded marrow colony-forming unit (CFUs) content increased while marrow CFUs self renewal capacity decreased as compared with unirradiated age-matched controls. Following irradiation experimental animals were monitored monthly for 10 to 12 months for marrow cellularity, CFUs content, and self renewal capacity. Shielded marrow cellularity and CFUs content remained elevated over age-matched controls throughout the period of observation. These findings are compatible with the requirement of the shielded hind limb to provide hematopoietic support for the remainder of the animal. Shielded marrow self renewal capacity, a measurement reflecting primitive hematopoietic stem cell function, remained depressed and did not recover with time. These experiments provide evidence for there being limitations on the self renewal capacity of the stem cell compartment. While the small amount of shielded marrow had sufficient capacity to support the animal its average self renewal capacity was permanently reduced.

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PubMed2002

The meso-angioblast: a multipotent, self-renewing cell that originates from the dorsal aorta and differentiates into most mesodermal tissues.

We have previously reported the origin of a class of skeletal myogenic cells from explants of dorsal aorta. This finding disagrees with the known origin of all skeletal muscle from somites and has therefore led us to investigate the in vivo origin of these cells and, moreover, whether their fate is restricted to skeletal muscle, as observed in vitro under the experimental conditions used. To address these issues, we grafted quail or mouse embryonic aorta into host chick embryos. Donor cells, initially incorporated into the host vessels, were later integrated into mesodermal tissues, including blood, cartilage, bone, smooth, skeletal and cardiac muscle. When expanded on a feeder layer of embryonic fibroblasts, the clonal progeny of a single cell from the mouse dorsal aorta acquired unlimited lifespan, expressed hemo-angioblastic markers (CD34, Flk1 and Kit) at both early and late passages, and maintained multipotency in culture or when transplanted into a chick embryo. We conclude that these newly identified vessel-associated stem cells, the meso-angioblasts, participate in postembryonic development of the mesoderm, and we speculate that postnatal mesodermal stem cells may be derived from a vascular developmental origin.

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PubMed2005

Stem cell self-renewal and cancer cell proliferation are regulated by common networks that balance the activation of proto-oncogenes and tumor suppressors.

Networks of proto-oncogenes and tumor suppressors that control cancer cell proliferation also regulate stem cell self-renewal and possibly stem cell aging. Proto-oncogenes promote regenerative capacity by promoting stem cell function but must be balanced with tumor suppressor activity to avoid neoplastic proliferation. Conversely, tumor suppressors inhibit regenerative capacity by promoting cell death or senescence in stem cells. For example, the polycomb family proto-oncogene, Bmi-1, is consistently required for the self-renewal of diverse adult stem cells, as well as for the proliferation of cancer cells in the same tissues. Bmi-1 promotes stem cell self-renewal partly by repressing the expression of Ink4a and Arf, tumor suppressor genes that are commonly deleted in cancer. Despite ongoing Bmi-1 expression, Ink4a expression increases with age, potentially reducing stem cell frequency and function. Increased tumor suppressor activity during aging therefore may partly account for age-related declines in stem cell function. Thus, networks of proto-oncogenes and tumor suppressors have evolved to coordinately regulate stem cell function throughout life. Imbalances within such networks cause cancer or premature declines in stem cell activity that resemble accelerated aging.

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PubMed1994

Evidence for a stromal cell-dependent, self-renewing B cell population in lymphoid follicles of the ileal Peyer's patch of sheep.

Lymphoid follicles of the ileal Peyer's patch (PP) of young sheep function as the major source of B cells and a site of immunoglobulin (Ig) receptor diversification. However, extensive cell death in culture has restricted investigations of ileal PP follicular (iPf)B cell biology. We investigated the possibility that sustained iPfB cell proliferation may require an interaction with mesenchymal stromal cells (SC). Four SC lines, cloned from lymphoid follicles of the ileal PP, and various sheep and xenogeneic mesenchymal cells were used to characterize the nature of iPfB cell-SC interactions. A sustained proliferative response was unique to iPfB cells, required iPfB cell-SC contact, and SC membranes functioned as intact SC to either enhance or inhibit iPfB cell proliferative responses. The iPfB cell proliferation in SC co-cultures was accompanied by extensive cell death and a slow decline in viable cell number. Flow cytometric analysis confirmed that viable lymphocytes, present in SC co-cultures, were immature B cells that expressed surface IgM, with either lambda or kappa. Ig light chain, and that SC co-culture inhibited iPfB cell differentiation. Finally, addition of soluble anti-sheep Ig to iPfB cell-SC co-cultures did not inhibit SC-dependent iPfB cell proliferation or iPfB cell binding to SC. These data indicate that an interaction between specific SC membrane molecules and non-Ig molecules of iPfB cells either supported or inhibited a self-renewing proliferative response by immature (sIgMLo, BAQ44A-) iPfB cells. Finally, SC-dependent iPfB cell proliferation was independent of T cells and extrinsic antigen which further suggests that a functionally distinct B cell population resides in lymphoid follicles of the ileal PP.

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PubMed2005

Jagged1 signals in the postnatal subventricular zone are required for neural stem cell self-renewal.

Neural stem cells (NSCs) in the postnatal mammalian brain self-renew and are a source of neurons and glia. To date, little is known about the molecular and cellular mechanisms regulating the maintenance and differentiation of these multipotent progenitors. We show that Jagged1 is required by mitotic cells in the subventricular zone (SVZ) and stimulates self-renewal of multipotent epidermal growth factor-dependent NSCs. Jagged1-expressing cells line the adult SVZ and are juxtaposed to Notch1-expressing cells, some of which are putative NSCs. In vitro, endogenous Jagged1 acts through Notch1 to promote NSC maintenance and multipotency. In vivo, reducing Jagged1/Notch1 signaling decreases the number of proliferating cells in the SVZ. In addition, soluble Jagged1 promotes self-renewal and neurogenic potential of multipotent neural progenitors in vitro. Our findings suggest a central role for Jagged1 in the NSC niche in the SVZ for maintaining a population of NSCs in the postnatal brain.

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PubMed2004

Plzf is required in adult male germ cells for stem cell self-renewal.

Adult germline stem cells are capable of self-renewal, tissue regeneration and production of large numbers of differentiated progeny. We show here that the classical mouse mutant luxoid affects adult germline stem cell self-renewal. Young homozygous luxoid mutant mice produce limited numbers of normal spermatozoa and then progressively lose their germ line after birth. Transplantation studies showed that germ cells from mutant mice did not colonize recipient testes, suggesting that the defect is intrinsic to the stem cells. We determined that the luxoid mutant contains a nonsense mutation in the gene encoding Plzf, a transcriptional repressor that regulates the epigenetic state of undifferentiated cells, and showed that Plzf is coexpressed with Oct4 in undifferentiated spermatogonia. This is the first gene shown to be required in germ cells for stem cell self-renewal in mammals.

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PubMed2003

Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation.

Stem cells persist throughout life by self-renewing in numerous tissues including the central and peripheral nervous systems. This raises the issue of whether there is a conserved mechanism to effect self-renewing divisions. Deficiency in the polycomb family transcriptional repressor Bmi-1 leads to progressive postnatal growth retardation and neurological defects. Here we show that Bmi-1 is required for the self-renewal of stem cells in the peripheral and central nervous systems but not for their survival or differentiation. The reduced self-renewal of Bmi-1-deficient neural stem cells leads to their postnatal depletion. In the absence of Bmi-1, the cyclin-dependent kinase inhibitor gene p16Ink4a is upregulated in neural stem cells, reducing the rate of proliferation. p16Ink4a deficiency partially reverses the self-renewal defect in Bmi-1-/- neural stem cells. This conserved requirement for Bmi-1 to promote self-renewal and to repress p16Ink4a expression suggests that a common mechanism regulates the self-renewal and postnatal persistence of diverse types of stem cell. Restricted neural progenitors from the gut and forebrain proliferate normally in the absence of Bmi-1. Thus, Bmi-1 dependence distinguishes stem cell self-renewal from restricted progenitor proliferation in these tissues.

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PubMed2001

[Stem cell and self-renewal].

Stem cells are defined as cells with the ability for self-renewal and differentiation. Hematopoietic stem cells are well known, and their application is useful for the treatment of various kinds of diseases. Recently, neural stem cells have been identified even in the adult brain, which has up to now been considered to be a tissue with no regenerative capacity. In addition, it has emerged that tissue stem cells can differentiate into various kinds of cells beyond their original characteristics. Here, we discuss the self-renewal mechanisms of embryonic stem (ES) cells, hematopoietic stem cells and neural stem cells.

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PubMed2002

Distinct roles for CREB-binding protein and p300 in hematopoietic stem cell self-renewal.

Hematopoietic stem cells (HSC) are tightly regulated through, as yet, undefined mechanisms that balance self-renewal and differentiation. We have identified a role for the transcriptional coactivators CREB-binding protein (CBP) and p300 in such HSC fate decisions. A full dose of CBP, but not p300, is crucial for HSC self-renewal. Conversely, p300, but not CBP, is essential for proper hematopoietic differentiation. Furthermore, in chimeric mice, hematologic malignancies emerged from both CBP(-/-) and p300(-/-) cell populations. Thus, CBP and p300 play essential but distinct roles in maintaining normal hematopoiesis, and, in mice, both are required for preventing hematologic tumorigenesis.

Alleles↗
PubMed2000

Somatic support cells restrict germline stem cell self-renewal and promote differentiation.

Stem cells maintain populations of highly differentiated, short-lived cell-types, including blood, skin and sperm, throughout adult life. Understanding the mechanisms that regulate stem cell behaviour is crucial for realizing their potential in regenerative medicine. A fundamental characteristic of stem cells is their capacity for asymmetric division: daughter cells either retain stem cell identity or initiate differentiation. However, stem cells are also capable of symmetric division where both daughters remain stem cells, indicating that mechanisms must exist to balance self-renewal capacity with differentiation. Here we present evidence that support cells surrounding the stem cells restrict self-renewal and control stem cell number by ensuring asymmetric division. Loss of function of the Drosophila Epidermal growth factor receptor in somatic cells disrupted the balance of self-renewal versus differentiation in the male germline, increasing the number of germline stem cells. We propose that activation of this receptor specifies normal behaviour of somatic support cells; in turn, the somatic cells play a guardian role, providing information that prevents self-renewal of stem cell identity by the germ cell they enclose.

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PubMed2002

Hematopoietic stem cells: self-renewing or aging?

Stem cells are defined by their extensive self-renewal properties, and yet there is abundant evidence of erosion of stem cell functioning during aging. Whereas intracellular repair and protection mechanisms determine the lifespan of an individual cell, here an argument is made that somatic stem cells determine the lifespan of an entire tissue, and thus play a key role in the organismal aging process. Recently it has been shown that the developmental potential of somatic stem cells may be far greater than previously anticipated. Although the mechanisms regulating stem cell plasticity are far from clear, it is challenging to discuss the potential relevance of these findings in the aging process.

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PubMed2004

Metabolic rate determines haematopoietic stem cell self-renewal.

The number of haematopoietic stem cells (HSCs) per animal is conserved across species. This means the HSCs need to maintain hematopoiesis over a longer period in larger animals. This would result in the requirement of stem cell self-renewal. At present the three existing models are the stochastic model, instructive model and the third more recently proposed is the chiaro-scuro model. It is a well known allometric law that metabolic rate scales to the three quarter power. Larger animals have a lower metabolic rate, compared to smaller animals. Here it is being hypothesized that metabolic rate determines haematopoietic stem cell self-renewal. At lower metabolic rate the stem cells commit for self-renewal, where as at higher metabolic rate they become committed to different lineages. The present hypothesis can explain the salient features of the different models. Recent findings regarding stem cell self-renewal suggest an important role for Wnt proteins and their receptors known as frizzleds, which are an important component of cell signaling pathway. The role of cGMP in the Wnts action provides further justification for the present hypothesis as cGMP is intricately linked to metabolic rate. One can also explain the telomere homeostasis by the present hypothesis. One prediction of the present hypothesis is with reference to the limit of cell divisions known as Hayflick limit, here it is being suggested that this is the result of metabolic rate in laboratory conditions and there can be higher number of cell divisions in vivo if the metabolic rate is lower.

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PubMed2006

Identifying genes important for spermatogonial stem cell self-renewal and survival.

Spermatogonial stem cells (SSCs) are the foundation for spermatogenesis and, thus, preservation of a species. Because of stem cell rarity, studying their self-renewal is greatly facilitated by in vitro culture of enriched biologically active cell populations. A recently developed culture method identified glial cell line-derived neurotrophic factor (GDNF) as the essential growth factor that supports in vitro self-renewal of SSCs and results in an increase in their number. This system is a good model to study mechanisms of stem cell self-renewal because of the well defined culture conditions, enriched cell population, and available transplantation assay. By withdrawing and replacing GDNF in culture medium, we identified regulated expression of many genes by using microarray analysis. The expression levels of six of these genes were dramatically decreased by GDNF withdrawal and increased by GDNF replacement. To demonstrate the biological significance of the identified GDNF-regulated genes, we examined the importance of the most responsive of the six, bcl6b, a transcriptional repressor. By using siRNA to reduce transcript levels, Bcl6b was shown to be crucial for SSC maintenance in vitro. Moreover, evaluation of Bcl6b-null male testes revealed degeneration and/or absence of active spermatogenesis in 24 +/- 7% of seminiferous tubules. These data suggest that Bcl6b is an important molecule in SSC self-renewal and validate the biological relevance of the GDNF-regulated genes identified through microarray analysis. In addition, comparison of data generated in this study to other stem cell types suggests that self-renewal in SSCs is regulated by distinctly different molecular mechanisms.

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PubMed2005

PTEN negatively regulates neural stem cell self-renewal by modulating G0-G1 cell cycle entry.

Previous studies have demonstrated that a small subpopulation of brain tumor cells share key characteristics with neural stem/progenitor cells in terms of phenotype and behavior. These findings suggest that brain tumors might contain "cancer stem cells" that are critical for tumor growth. However, the molecular pathways governing such stem cell-like behavior remain largely elusive. Our previous study suggests that the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) tumor suppressor gene, one of the most frequently mutated genes in glioblastomas, restricts neural stem/progenitor cell proliferation in vivo. In the present study, we sought to determine the role of PTEN in long-term maintenance of stem cell-like properties, cell cycle entry and progression, and growth factor dependence and gene expression. Our results demonstrate an enhanced self-renewal capacity and G(0)-G(1) cell cycle entry and decreased growth factor dependency of Pten null neural/stem progenitor cells. Therefore, loss of PTEN leads to cell physiological changes, which collectively are sufficient to increase the pool of self-renewing neural stem cells and promote their escape from the homeostatic mechanisms of proliferation control.

Animals↗
PubMed2005

Conservation of spermatogonial stem cell self-renewal signaling between mouse and rat.

Self-renewal of spermatogonial stem cells (SSCs) is the foundation for maintenance of spermatogenesis throughout life in males and for continuation of a species. The molecular mechanism underlying stem cell self-renewal is a fundamental question in stem cell biology. Recently, we identified growth factors necessary for self-renewal of mouse SSCs and established a serum-free culture system for their proliferation in vitro. To determine whether the stimulatory signals for SSC replication are conserved among different species, we extended the culture system to rat SSCs. Initially, a method to assess in vitro expansion of SSCs was developed by using flow cytometric analysis, and, subsequently, we found that a combination of glial cell line-derived neurotrophic factor, soluble glial cell line-derived neurotrophic factor-family receptor alpha-1 and basic fibroblast growth factor supports proliferation of rat SSCs. When cultured with the three factors, stem cells proliferated continuously for >7 months, and transplantation of the cultured SSCs to recipient rats generated donor stem cell-derived progeny, demonstrating that the cultured stem cells are normal. The growth factor requirement for replication of rat SSCs is identical to that of mouse; therefore, the signaling factors for SSC self-renewal are conserved in these two species. Because SSCs from many mammals, including human, can replicate in mouse seminiferous tubules after transplantation, the growth factors required for SSC self-renewal may be conserved among many different species. Furthermore, development of a long-term culture system for rat SSCs has established a foundation for germ-line modification of the rat by gene targeting technology.

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